Inhibition of P53/miR-34a improves diabetic endothelial dysfunction via activation of SIRT1
Inhibition of P53/miR-34a improves diabetic endothelial dysfunction via activation of SIRT1
复制标题
抑制 P53/miR-34a 通过激活 SIRT1 改善糖尿病内皮功能障碍
DOI：
10.1111/jcmm.14253
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发表时间：
2019-05-01
影响因子：
5.3
通讯作者：
Wu, Hao
中科院分区：
文献类型：
--
作者：
Wu, Junduo;Liang, Wenzhao;Wu, Hao
内皮功能障碍导致糖尿病大血管并发症，导致高死亡率。最近的研究结果表明P53在内皮功能障碍中的致病作用，鼓励研究P53抑制对糖尿病内皮功能障碍的影响。因此，高葡萄糖（HG）处理的内皮细胞（EC）进行pifithrin-alpha（PFT-alpha）-alpha特异性抑制剂P53，或P53-小干扰RNA（siRNA），这两个减弱HG诱导的内皮炎症和氧化应激。此外，PFT-α或P53-siRNA抑制P53抑制了P53乙酰化，降低了microRNA-34 a（miR-34 a）水平，导致sirtuin 1（SIRT 1）蛋白水平显著增加。有趣的是，miR-34 a抑制剂（miR-34 a-I）和PFT-α增加SIRT 1蛋白水平，并以相似的程度减轻HG诱导的内皮炎症和氧化应激;然而，PFT-α的这些作用被miR-34 a模拟物完全消除。此外，EX-527或Sirt 1-siRNA对SIRT 1的抑制作用完全消除了miR-34 a-I对HG诱导的内皮炎症和氧化应激的保护作用。此外，在链脲佐菌素诱导的糖尿病小鼠的动脉中，PFT-alpha和miR-34 a-I都挽救了由高脂血症引起的炎症、氧化应激和内皮功能障碍。因此，本研究发现了导致内皮功能障碍的P53/miR-34 a/SIRT 1途径，这表明P53/miR-34 a抑制可能是治疗糖尿病大血管疾病的可行策略。
Endothelial dysfunction contributes to diabetic macrovascular complications, resulting in high mortality. Recent findings demonstrate a pathogenic role of P53 in endothelial dysfunction, encouraging the investigation of the effect of P53 inhibition on diabetic endothelial dysfunction. Thus, high glucose (HG)-treated endothelial cells (ECs) were subjected to pifithrin-alpha (PFT-alpha)-alpha specific inhibitor of P53, or P53-small interfering RNA (siRNA), both of which attenuated the HG-induced endothelial inflammation and oxidative stress. Moreover, inhibition of P53 by PFT-alpha or P53-siRNA prohibited P53 acetylation, decreased microRNA-34a (miR-34a) level, leading to a dramatic increase in sirtuin 1 (SIRT1) protein level. Interestingly, the miR-34a inhibitor (miR-34a-I) and PFT-alpha increased SIRT1 protein level and alleviated the HG-induced endothelial inflammation and oxidative stress to a similar extent; however, these effects of PFT-alpha were completely abrogated by the miR-34a mimic. In addition, SIRT1 inhibition by EX-527 or Sirt1-siRNA completely abolished miR-34a-I's protection against HG-induced endothelial inflammation and oxidative stress. Furthermore, in the aortas of streptozotocin-induced diabetic mice, both PFT-alpha and miR-34a-I rescued the inflammation, oxidative stress and endothelial dysfunction caused by hyperglycaemia. Hence, the present study has uncovered a P53/miR-34a/SIRT1 pathway that leads to endothelial dysfunction, suggesting that P53/miR-34a inhibition could be a viable strategy in the management of diabetic macrovascular diseases.